Helicobacter pylori Modulated Host Immunity in Gastric Cancer Patients With S-1 Adjuvant Chemotherapy.

BACKGROUND: Paradoxically, Helicobacter pylori-positive (HP+) advanced gastric cancer patients have a better prognosis than those who are HP-negative (HP-). Immunologic and statistical analyses can be used to verify whether systemic mechanisms modulated by HP are involved in this more favorable outcome. METHODS: A total of 658 advanced gastric cancer patients who underwent gastrectomy were enrolled. HP infection, mismatch repair, programmed death-ligand 1 (PD-L1) and CD4/CD8 proteins, and microsatellite instability were analyzed. Overall survival (OS) and relapse-free survival (RFS) rates were analyzed after stratifying clinicopathological factors. Cox proportional hazards regression analysis was performed to identify independent prognostic factors. RESULTS: Among 491 patients that were analyzed, 175 (36%) and 316 (64%) patients were HP+ and HP-, respectively. Analysis of RFS indicated an interaction of HP status among the subgroups for S-1 dose (Pinteraction = .049) and PD-L1 (P = .02). HP+ patients in the PD-L1- group had statistically higher 5-year OS and RFS than HP- patients (81% vs 68%; P = .0011; hazard ratio [HR] = 0.48, 95% confidence interval [CI] = 0.303 to 0.751, and 76% vs 63%; P = .001; HR = 0.508, 95% CI = 0.335 to 0.771, respectively). The 5-year OS and RFS was also statistically higher for HP+ compared with HP- patients in the "PD-L1- and S-1-r educed" group (86% vs 46%; P = .001; HR = 0.205, 95% CI = 0.07 to 0.602, and 83% vs 34%; P = .001; HR = 0.190, 95% CI = 0.072 to 0.498, respectively). Thus, HP status was identified as one of the most potentially important independent factors to predict prolonged survival. CONCLUSION: This retrospective study suggests that an HP-modulated host immune system may contribute to prolonged survival in the absence of immune escape mechanisms of gastric cancer.

Steroidogenesis in ovarian-like mesenchymal stroma of hepatic and pancreatic mucinous cystic neoplasms.

STEROIDOGENESIS IN HEPATIC MUCINOUS CYSTIC NEOPLASM: Aim Mucinous cystic neoplasms (MCNs) occur in the ovary, pancreas, and retroperitoneum but very rarely in the liver. Mucinous cystic neoplasms are known to harbor ovarian-like mesenchymal stroma (OLS) expressing progesterone and estrogen receptors. In this study we evaluated steroidogenesis in OLS of 25 hepatic MCNs and 24 pancreatic MCNs. Methods Both steroid receptors and steroidogenic factors were immunohistochemically evaluated using H-scores and results were compared with those in 15 ovarian MCNs and 10 normal ovaries. Results Androgen receptor (AR) H-scores in OLS were significantly higher in hepatic, pancreatic, and ovarian MCN than those in normal ovaries. H-scores of cytochrome P450 17α-hydroxylase/c17-20 lyase (P450c17) and 5α-reductase-1 (5αRED-1) in the stroma were significantly higher in OLS of hepatic and pancreatic MCN than in the stroma of ovarian MCN and normal ovary. In tumor epithelium, AR H-scores were significantly higher in hepatic and pancreatic MCN than in ovarian MCN. In both hepatic and pancreatic MCN, a significant positive correlation was detected between AR H-score in the epithelium and P450c17 H-score in OLS (hepatic MCN: Pearson's r = 0.446, P = 0.025; pancreatic MCN: r = 0.432, P = 0.035). In pancreatic MCN, a significantly positive correlation was detected between AR H-score in the tumor epithelium and 5αRED-1 H-score in OLS (Pearson's r = 0.458, P = 0.024). Conclusions These results indicated that locally produced androgens in OLS could be pivotal for tumorigenesis of both hepatic and pancreatic MCN and influence epithelial cells, possibly in a paracrine fashion, which could represent biological significance of OLS in these neoplasms.

Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: Limited information exists regarding beneficial effects of Helicobacter pylori. To examine the effect in advanced gastric cancer, we compared survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status. METHODS: A cohort of 491 patients who underwent R0 resection for locally advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan was included. H. pylori infection status, was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication. RESULTS: H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS (hazard ratio [HR] 0.593, 95% confidence interval [CI] 0.417-0.843; P = 0.003]) and DFS (HR 0.679, 95%CI 0.492-0.937; P = 0.018). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive. CONCLUSIONS: The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.

Analysis of PIK3CA mutations and PI3K pathway proteins in advanced gastric cancer.

BACKGROUND: Although surgery and chemotherapy have extended advanced gastric cancer patient survival, some patients still experience relapse and metastasis. We postulated that PI3K pathway proteins could be prognostic biomarkers for the advanced gastric cancer patients. METHODS: A retrospective cohort of 160 advanced gastric cancer patients receiving potentially curative surgery with/without chemotherapy was investigated for PIK3CA mutation and PI3K pathway protein level in the context of overall survival and relapse-free survival. RESULTS: Thirteen patients (13 of 111, 11.7%) had PIK3CA mutations in codon 545, whereas one patient (1 of 94, 1.1%) had a mutation in PIK3CA codon 1047. PI3K pathway protein immunohistochemistry demonstrated that phosphorylated AKT positive [p-AKT (+)] patients in the surgery-only group had a good prognosis in terms of overall survival and relapse-free survival. No significant association between PIK3CA mutations and PI3K pathway protein level was seen. CONCLUSIONS: This study revealed that (1) PIK3CA hotspot mutations occurred with low frequency in gastric cancer; (2) PIK3CA hotspot mutations were not directly associated with PI3K pathway activation; and (3) p-AKT (+) may be a biomarker for better outcomes for gastric cancer patients undergoing gastrectomy regardless of the PIK3CA mutation status.

[Intravascular papillary endothelial hyperplasia of the lung].

We report a rare case of pulmonary intravascular papillary endothelial hyperplasia. The patient was a 63-year-old male. Multiple lung nodules were noted on chest computed tomography( CT) at preoperative check for gastric cancer. Metastatic lung tumor was suspected, and partial resection of the right lung was performed. Histopathologic examination revealed papillary proliferation lined by endothelial cells and a hematoma. Immunohistochemically, the endothelial cells were positive for CD31/CD34 and factor VIII related antigen.

The correlation of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification with prognosis and EGFR mutation in lung adenocarcinoma.

BACKGROUND: The purpose of this study was to validate the prognostic effect and the frequency of mutations in the gene expressing epidermal growth factor receptor (EGFR) in lung adenocarcinoma of Japanese patients, on the basis of the new adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. METHODS: The new classification was used to reclassify 486 adenocarcinomas. The percentage of each histopathologic subtype and the predominant pattern were determined. EGFR mutation was also investigated. The relationship between these results and clinicopathologic backgrounds was investigated statistically. RESULTS: No patients with adenocarcinoma in situ or minimally invasive adenocarcinoma died within the follow-up periods, followed by patients with lepidic predominant. Patients with papillary or acinar predominant, or invasive mucinous adenocarcinoma, showed almost similar overall survival (OS). The patients with solid predominant and micropapillary predominant showed the worst OS. Multivariate analysis showed that the new classification was an independent predictor of OS. The frequency of EGFR mutation was adenocarcinoma in situ (62%), minimally invasive adenocarcinoma (60%), lepidic (77%), acinar (49%), papillary (50%), solid (28%), micropapillary (43%), and invasive mucinous adenocarcinoma (0%). CONCLUSIONS: This new adenocarcinoma classification is a very useful predictive marker to plan and determine a therapeutic strategy for lung adenocarcinoma.

Positive intraoperative pleural lavage cytology is a predictive marker of disease recurrence in stage I lung adenocarcinoma.

OBJECTIVES: This study aimed at analysing the relationship between the pleural lavage cytology (PLC) status and clinicopathological characteristics, including the outcome of examined patients and tumour recurrence sites in surgically resected stage I non-small-cell lung carcinoma. METHODS: From April 2002 to August 2012, PLC was performed immediately after thoracotomy in 428 consecutive patients undergoing pulmonary resection for lung cancer. The relationship between clinicopathological characteristics and the PLC status was retrospectively analysed. RESULTS: The frequency of PLC-positive results was 4.4%, and larger tumour size, stage IB and pleural invasion were found more frequently in PLC-positive patients. Patients with a PLC-positive status had significantly worse disease-free survival (DFS) than those with a PLC-negative status (PLC positive versus PLC negative: hazard ratio [HR] = 2.79, 95% confidence interval [CI]: 1.4-5.57, P < 0.004; 5-year DFS: 46.6 vs 76.5%). With regard to the PLC status and histological type, adenocarcinoma was associated with a worse DFS in PLC-positive patients when compared with PLC-negative patients (5-year DFS: 38.1 vs 81.1%, P < 0.001). In multivariate analysis, PLC status remained significantly associated with DFS in patients with a PLC-positive status having an increased risk of recurrence, compared with PLC-negative patients (HR = 2.494, 95% CI: 1.241-5.011, P = 0.01) only in the case of adenocarcinoma. CONCLUSIONS: Our current study showed the clinicopathological characteristics associated with PLC status and demonstrated that PLC status was an independent predictor of increased recurrence in stage I lung adenocarcinoma.

[Comparison of HER2 immunohistochemical results for advanced gastric cancer obtained on using 3 different antibodies].

We compared the results of immunohistochemical assessment of HER2 expression in 107 samples of advanced gastric cancer on using 3 currently used antibodies. Expression was scored as 0 to 3+, and equivocal or discordant cases were subjected to fluorescence in situ hybridization(FISH)analysis. HER2 scores of 2+or 3+were noted in 16.8% of cases(18/ 107)using SV2-61g, in 29.9% of cases(32/107)using Dako HercepTest, and in 34.6% of cases(37/107)using 4B5. The results of the HER2 test differed according to the antibodies used for immunohistochemistry preceding FISH analysis, and the HER2 positive rates after the FISH analysis were 14.0%(15/107)using SV2-61g, 19.6% (21/107)using Dako HercepTest, and 22.4% (24/107)using 4B5. Thus, therapeutic decisions might be considerably influenced by the antibody used for the HER2 test.

Prognostic impact and initial recurrence site of lymphovascular and visceral pleural invasion in surgically resected stage I non-small-cell lung carcinoma.

OBJECTIVES: This study aimed to analyse and validate the prognostic impact and effect of the initial recurrence site of lymphovascular and visceral pleural invasion (VPI) on survival outcomes for Stage I non-small-cell lung carcinoma (NSCLC). METHODS: We retrospectively reviewed 433 patients undergoing resection of Stage I NSCLC. The relationship between the clinicopathological background and the pathological variables, lymphovascular invasion (LVI) and VPI, was evaluated by univariate and multivariate analyses. RESULTS: Lymphovascular and VPI was observed in 41 and 45 patients, respectively. On univariate analysis, the presence of LVI was associated with a significant decrease in relapse-free survival (RFS) (P < 0.001) and overall survival (OS) (P < 0.001). The RFS of the patients of Stage IB with LVI was worse than the RFS of those of Stage IIA (T2aN1 and T2bN0)/IIB (T3N0), and similar to the RFS of those of Stage IIB (T2bN1). The presence of VPI was also associated with a significant decrease in RFS (P < 0.001) and OS (P = 0.01). On multivariate analysis, LVI was found to be an independent predictor of both decreased RFS and decreased OS. However, VPI was not an independent predictor of both. Recurrence was seen in 68 patients. As an initial recurrence site, distant recurrence was seen in 32 patients and local recurrence, in 36. The proportion of local recurrence was significantly higher in the patients with VPI than in those without VPI compared with between the patients with LVI and those without LVI. CONCLUSIONS: We propose that LVI and/or VPI may be a candidate marker to determine adjuvant therapy or a more careful follow-up for these patients.

New IASLC/ATS/ERS classification and invasive tumor size are predictive of disease recurrence in stage I lung adenocarcinoma.

INTRODUCTION: The purpose of this study is to analyze and validate the prognostic impact of the new lung adenocarcinoma (ADC) classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society and invasive tumor size in stage I lung ADC of Japanese patients. METHODS: We reclassified 191 stage I ADCs according to the new classification. The percentage of each histological subtype and the predominant type were determined. In addition, both total tumor size and invasive tumor size were examined. The relationship between these results and clinicopathological backgrounds was investigated statistically. RESULTS: The 5-year disease-free survival (DFS) of adenocarcinoma in situ and minimally invasive adenocarcinoma was 100%; lipidic-predominant ADCs, 94.9%; papillary-predominant ADCs, 85.4%; acinar-predominant ADCs, 89.7%; and solid-predominant ADCs, 54%. The predominant growth pattern was significantly correlated with DFS (p < 0.001, overall). With regard to tumor size, total tumor size was not correlated with DFS (p = 0.475, overall), however, invasive tumor size was significantly correlated with DFS (≤ 0.5 cm/ > 0.5 cm, ≤ 1 cm/ >1 cm, ≤ 2 cm/>2 cm, ≤ 3 cm/ >3 cm, 100%/91.5%/85.9%/80.8%/66.7%% in 5-year DFS) (p = 0.006, overall). A multivariate analysis showed solid-predominant and invasive tumor size were independent predictors of increased risk of recurrence (solid versus nonsolid: hazard ratio = 4.08, 95% confidence interval:1.59-10.5, p = 0.003; invasive tumor size: hazard ratio = 2.04, 95% confidence interval:1.14-3.63, p = 0.016). CONCLUSION: : The new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society ADC classification and invasive tumor size are very useful predictors of recurrence of stage I ADCs in Japanese patients.

Multiple carcinoid tumors of the rectum: report of two cases suggesting the origin of carcinoid tumors.

Two cases of multiple carcinoid tumors of the rectum with numerous micronests of carcinoid tumors are reported. The patients were 51- and 58-year-old males. Many carcinoid tumors and numerous carcinoid micronests were found in the resected rectum; the total number of carcinoid tumors, groups of micronests, and solitary micronests was 69 in the first case and 62 in the second case. The micronests, consisting of a few to many endocrine cells, were observed in the lamina propria, muscularis mucosa, and/or submucosa. Micronests increased in number, gathered and formed carcinoid tumors, which were up to 8 mm in diameter. It was found that a nest of the carcinoid tumors in the lamina propria showed continuity with the endocrine cells of a crypt in the different carcinoid tumors in both cases. The carcinoid tumor and micronest infiltrated the nerves and ganglions in the muscularis mucosa and submucosa. Nests of the carcinoid tumors and micronests were surrounded by S-100-positive cells. Lymph node metastases of the carcinoid tumor were found in both cases. Rectal carcinoid tumors may originate from endocrine cells of the crypts, and multiple carcinoid tumors may occur heterogeneously.

Hepatic portal venous gas associated with severe graft-versus-host disease of the gastrointestinal tract.

We report a 67-year-old woman who was diagnosed with hepatic portal venous gas associated with severe graft-versus-host disease (GVHD) of the gastrointestinal tract. The patient received allogenic peripheral blood stem cell transplantation from a haploidentical son against Philadelphia chromosome-positive acute lymphocytic leukemia. The patient developed grade 3 intestinal GVHD on day 90 from the transplantation. On day 149, she presented septic shock and computed tomography (CT) scan revealed hepatic portal venous gas (HPVG); an ileocecal resection was performed immediately. The damage of gastrointestinal mucosa by GVHD resulted in the invasion of gas-producing bacteria. Although HPVG-associated gastrointestinal GVHD is extremely rare, we should pay special attention to this pathogenesis.

Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers.

To confirm the clinical significance of NF-κB and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-κB and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-κB(+) and JNK(-) subgroups in both gastric (NF-κB(+), p = 0.0002, HR11.7. 95%CI3 3.2-43.4; JNK(-), p = 0.0302, HR4.4, 95%CI 1.2-16.6) and colon (NF-κB(+), p = 0.0038, HR36.9, 95%CI 3.2-426.0; JNK(-), p = 0.0098, HR3.2, 95%CI 1.3-7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-κB and JNK, while 5-FU exposure of these cell lines only induced NF-κB, suggesting that NF-κB plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-κB increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers.

Comparison of HER2 immunohistochemical results using a monoclonal antibody (SV2-61γ) and a polyclonal antibody (for Dako HercepTest) in advanced gastric cancer.

We compared a monoclonal antibody (SV2-61γ) and a polyclonal antibody (Dako HercepTest) in immunohistochemical assessments of human epidermal growth factor receptor 2 (HER2) expression in 73 samples of advanced gastric cancer. Results were scored as 0 to 3+, and equivocal or discordant (SV2-61γ/Dako HercepTest = 0/2+, 0/3+, 1+/3+ or 2+/3+) cases were subjected to fluorescence in situ hybridization (FISH) analysis. The frequencies of HER2 scores of 2+ or 3+ were 15.1% (11/73) using SV2-61γ and 38.4% (28/73) using Dako HercepTest. All of the equivocal or discordant cases with a HER2 score of 3+ using Dako HercepTest exhibited amplification of the HER2 gene regardless of the HER2 score determined with SV2-61γ. The results of the HER2 tests differed according to the antibodies used for immunohistochemistry that preceded FISH analysis, being 15.1% (11/73) using SV2-61γ and 23.3% (17/73) using Dako HercepTest. Thus, therapeutic decisions might be markedly influenced by the selection of antibody used in the HER2 test.

[A case of curatively resected locally advanced cancer of the pancreatic body treated by distal pancreatectomy with en bloc celiac axis resection after neoadjuvant chemotherapy].

A 68-year-old man with locally advanced pancreatic body cancer invading the celiac axis(CA, including common hepatic artery)and in contact with the superior mesenteric artery(SMA)underwent 2 courses of neoadjuvant chemotherapy(NAC); gemcitabine hydrochloride(GEM 1,000 mg/m / / 2, on day 1 and 15)and S-1(100mg/m2day, 2-weeks of continuous administration followed by 1-week rest). The tumor volume and the contact area to SMA were greatly diminished. All tumor markers were reduced. He underwent R0 resection by distal pancreatectomy with en bloc celiac axis resection(DP-CAR). After the surgery, he could continue adjuvant chemotherapy; (GEM 1,000 mg/m2)only twice because of malnutrition. Nine months later CT revealed local recurrence and multiple lung metastases. The patient died 371 days after surgery. Appropriate NAC can contribute to R0 resection in locally advanced pancreatic cancer.

Synchronous Double Malignant Tumors Consisting of Stomach and Hodgkin's Lymphoma with Collision between Gastric Adenocarcinoma and Hodgkin's Lymphoma in the Stomach.

We report the rare case of a 72-year-old man with double cancers (gastric adenocarcinoma and Hodgkin's lymphoma) with collision between gastric adenocarcinoma and Hodgkin's lymphoma. Abdominal computed tomography showed increased wall thickness in the fundus region of the stomach and multiple lymph node swellings in the lesser curvature, periceliac and left cardial regions. Upper gastrointestinal endoscopy showed an ulcer approximately 5 cm in diameter with a malignant appearance in the fundus region of the stomach. On histopathologic examination, two completely different tumors were recognized in the stomach. One tumor was a poorly differentiated adenocarcinoma characterized by poorly developed tubular structures associated with prominent lymphoid infiltration of the stroma. The other tumor was found to have proliferated in the wall of the stomach, with diffuse granulomatous lesions and bordering the adenocarcinoma. Large atypical lymphoid cells with prominent nucleoli and enlarged mononuclei or multinuclei were seen in the latter tumor. Hodgkin's lymphoma was also found in the swollen lesser curvature lymph nodes. As a result, gastric adenocarcinoma and metastasis of Hodgkin's lymphoma were collided in the stomach. In conclusion, this case might be helpful in exploring the occurrence mechanism of tumor collision between lymphoma and carcinoma.

Peripheral T-cell lymphoma arising from an intraglandular lymph node in the parotid gland: a case report and literature review.

T/NK-cell lymphoma of the salivary gland is rare. A 58-year-old man complained of a tumor mass in the left parotid gland region and he was diagnosed to have a left parotid tumor. The tumor was subsequently resected, revealing a diffuse growth pattern of medium to large sized atypical cells. The tumor was surrounded by fibrous connective tissue in the form of a capsule, and those were positive for CD3, CD4, CD5 and CD30, but negative for Bcl2, CD8, CD10, CD15, CD20, CD25, CD56, CD79a, CD246, EMA, granzyme B, TdT and TIA-1. There was no molecular evidence of Epstein-Barr virus (EBV) infection. It was diagnosed as peripheral T-cell lymphoma (PTCL) arising from an intraglandular lymph node in the parotid gland. In conclusion, Only 17 cases of primary T/NK-cell lymphoma of the salivary glands have been recorded until now, and the characteristics of these are not clear yet. Additional study is needed.

Inverse correlation between EGFR mutation and FHIT, RASSF1A and RUNX3 methylation in lung adenocarcinoma: relation with smoking status.

BACKGROUND: Epidemiological studies have demonstrated a causal link between tobacco smoking and lung cancer. However, lung adenocarcinoma (AC) is also frequently found in non-smokers compared with other non-small cell lung carcinoma (NSCLC) subtypes. MATERIALS AND METHODS: Mutations of both epithelial growth factor receptor (EGFR) and KRAS, and the methylation status of 10 tumor suppressor or tumor-related genes were examined in 62 ACs, and the relationship with smoking status, and the relationship between the genetic alterations and epigenetic alterations were investigated. RESULTS: The frequency of EGFR mutation was strongly correlated with smoking status, and the frequency of KRAS mutation, and methylation of retinoic acid receptor beta (RAR-ß), p16, FHIT and RASSF1A were weakly related with smoking status. Inverse correlation was found between EGFR mutation and FHIT, RASSF1A and RUNX3 methylation. CONCLUSION: Tobacco smoking is correlated with the frequencies of EGFR and KRAS mutations as to pathogenesis of ACs.

MAGE expressions mediated by demethylation of MAGE promoters induce progression of non-small cell lung cancer.

BACKGROUND: The MAGE gene encodes cancer/testis antigens that are recognized on melanoma cells by autologous cytolytic T lymphocytes. These genes are expressed in various tumor cells, but not in healthy tissues except for the testis and placenta. MAGE expression is known to be activated by promoter demethylation. MATERIALS AND METHODS: The expression of MAGE-A1 and -A3 and promoter methylation of MAGE-A1 and -A3 was investigated in 67 non-small cell lung cancer (NSCLC) specimens and their correlation with clinicopathological parameters was elucidated. RESULTS: Expression of MAGE-A1 and -A3 was detected in 29.9% and 38.8% of the cases. Demethylation of MAGE-A1 and -A3 was detected in 41.8% and 46.3% of the cases. In 18 (of 20) cases, MAGE-A1 expression showed demethylation of MAGE-A1 and in 24 (of 26) cases MAGE-A3 expression showed demethylation of MAGE-A3. The patients with MAGE expression had a worse prognosis than those with no MAGE expression. CONCLUSION: MAGE expression mediated by demethylation of MAGE promoters is associated with aggressive progression of NSCLC.